Synergistic antiseptic compositions

ABSTRACT

COMPOSITIONS POSSESSING ANTIBACTERIAL ACTIVITY THROUGH THE EFFECT OF SYNERGISTIC MIXTURES OF 2,2&#39;&#39;-METHYLENE-BIS(3,4,6-TRICHLOROPHENOL) - DI - (N - METHYLCARBAMATE) AND 3,3&#39;&#39;,4,4&#39;&#39;-TETRACHLOROCARBANILIDE.

United States Patent 3,703,471 SYNERGISTIC ANTISEPTIC COMPOSITIONS Moueeb Zakaria, Chicago, Leo A. Raphaelian, Wilmette, David Taber, Evanston, and James Brown, Jr., Chicago, Ill., assignors to Armour-Dial, Inc., Chicago, Ill. N0 Drawing. Filed July 20, 1970, Ser. No. 56,719 Int. Cl. Clld 3/48 US. Cl. 252-107 4 Claims ABSTRACT OF THE DISCLOSURE Compositions possessing antibacterial activity through the effect of synergistic mixtures of 2,2'-methylene-bis- (3,4,6-trichlorophenol) di (N methylcarbamate) and 3,3',4,4'-tetrachlorocarbanilide.

The present invention relates to antiseptic compositions which possess synergistic activities through the use of mixtures of antibacterial agents. More specifically the present invention relates to a mixture of 3,3',4,4-tetrachlorocarbanilide and a di-methylcarbamate, 2,2'-methylene-bis-(3,4,6-trichlorophenol)-di-(N methylcarbamate) having the formula:

II OENHCH; (')CNHCH:

Antiseptic or antibacterial agents have been used in soaps and other detergent and cosmetic cleansing preparations for a considerable period of time. One of the most widely used types of such agents has been certain halogenated bisphenols, such as those described in US. Pat. 2,535,077, and particularly hexachlorophene [2,2'-methylene-bis 3,4,6-trichlorophenol) The past decade has seen major improvements in antibacterial systems for cleaning compositions like soap, such as by the introduction of new antibacterial agents and the introduction of synergistic antibacterial systems. However, the number of compounds and systems which have been developed and are suitable from technical, safety and economic points of view has been really quite small. In order for a new antibacterial agent or system to become part of a successful product such as a toilet soap, the compounds must possess broad spectrum antibacterial activity. Such antibacterial activity must be maintained in the presence of soap or other cleansing agents. Chemical stability in the presence of the cleansing composition must be maintained, as 'well as nonreactivity with the other components of the cleansing composition such as perfumes, antioxidants, brighteners and the like. In addition, the product must evidence mildness and safety for general use in the finished product.

Thus relatively few antibacterial agents or bacteriostats and systems have been found which meet all of the above requirements.

In efforts to playdown the drawbacks of known and effective antibacterial agents, recent attention has been focused upon the development of synergistic bacteriostatic systems. The term synergistic activity as applied herein means an antibacterial effect which is greater in combination than the sum of the antibacterial effects of the separate components. It must be recognized that the occurrence of synergistic activity is highly unexpected and unusual, since the fact that a particular compound may exhibit synergism with a certain other compound generally does not carry over to additional compounds even though they may have similar structures. Further synergistic activity is generally quite limited even as to the ratios and proportions of the individual ingredients exhibiting synergism. An example of known synergism may be found in the Casely and Noel US. Pat. 3,177,-

disclosing synergistic binary antibacterial systems comprising mixtures of certain isomeric trihalogenated carbani'lides, particularly TCC, with a number of halogenated bisphenols and alkylated halogenated bisphenols, particularly hexachlorophene. The discovery of such synergism was extremely important in providing soap manufactures with the ability to not only provide cleansing compositions having a high level of antibacterial activity, but also to maintain such activity with a greatly reduced concentration of antibacterial agents. The latter point is of further importance in allowing the substantial decrease of the amount of hexachlorophene employed in the antibacterial composition, thereby greatly reducing the tendency of the composition to discolor upon prolonged exposure to sunlight.

In accordance with the present invention, it has been found that mixtures of 3,3',4,4'-tetrachlorocarbanilide and 2,2'-methylene-bis-(3,4,6-trichlorophenol) di (N- methylcarbamate) exhibit synergistic antibacterial activity, and that this activity is maintained unimpaired when such mixtures are incorporated into various cleansing compositions such as soap and other detergent and cosmetic preparations.

It is therefore an object of the present invention to provide antibacterial compositions which include as antibacterial agents a synergistic combination of 3,3',4,4'- tetrachlorocarbanilide and 2,2'-methylene-bis-(3,4,6-trichlorophenol)-di- (N-methylcarbamate) It is a further object of this invention to provide antibacterial agents which are effective in soap and in other detergent and cosmetic mediums.

Other objects and advantages and a fuller understanding of our invention will become apparent from the ensuing description and examples.

In a specific embodiment, our invention may be exemplified by a soap composition containing as the antibacterial agent a synergistic mixture of 3,3',4,4'-tetrachlorocarbanilide and 2,2 methylene bis (3,4,6 trichlorophenol)-di-(N-methylcarbamate) and wherein the ratio of tetrachloroearbanilide to the di-(N-methylcarbamate) present in the soap in parts by weight is about 1 to 1.95 to about 0.25 to 1.95.

It is found that when the tetrachlorocarbanilide and the di-(N-methylcarbamate) as set forth above are used together, germicidal effects are achieved which are substantially greater than the mere total of the individual effects of the individual ingredients. Such effects are important in cases Where it is desirable to increase the activity of the known bacteriostat ingredient without emp1oy ing higher concentrations. Such effects are also important in cases where it is desirable to reduce the total concentration of the antibacterial agents while at the same time maintaining a desired level of antibacterial effect, or to reduce the concentration of the known bacteriostat thereby lowering the incidence of drawbacks to the use of that bacteriostat in the product while maintaining high antibacterial effectiveness.

The present invention is still further important in that the above synergistic phenomena occur even at the high pH conditions existing in detergent formulations such as soap.

Our invention may be further illustrated by the following specific example:

3 EXAMPLE The agents are evaluated for antibacterial effectiveness by means of a modified agar streak method utilizing a soap solution (100,000 p.p.m. of soap) containing the agents. Briefly the test consists of making serial dilutions of a 10 ml. solution containing a specific quantity of the agents(s) in dimethyl formamide which are then dispersed into 80 ml. of distilled water containing 10 grams of soap. All solutions are maintained at 60 C. until they are dispensed. Aliquots of the dilutions containing concentrations of the bacteriostatic agents ranging from about 0.02 to 10 p.p.m. at 50 C. are thoroughly dispersed into measured amounts of nutrient agar. Plates are poured, allowed to solidify, and streaked with a standard 4 mm. loopful of a 24-hour broth culture of Staphylococcus aureus FDA 209. After incubation for 24 hours at 37 C. the bacteriostatic end point is determined. The bacteriostatic end point, hereinafter called the minimum inhibitory concentration (MIC), represents the minimum concentration in parts per million by weight of the bacteriostatic agent necessary to inhibit all growth of the innoculent organism. No particular minimum inhibitory concentration has been established to determine the usefulness of a bacteriostatic agent, although the lower the end point, the better the bacteriostatic activity and the smaller the amount of the agent necessary to maintain a particular degree of effectiveness. The soap utilized for this evaluations was a neutral white toilet soap containing about by weight of sodium coco soap and 80% by weight of sodium tallow soap.

Using the modified agar streak method as set forth above it was determined that a soap solution containing 1.95% of the 2,2'-methylene-bis-(3,4,6-trichlorophenol)- di-(N-methylcarbmate) had an end point or MIC of 0.22 p.p.m. Solutions were made of 1%, 0.75%, 0.5% and 0.25% of the tetrachlorocarbanilide and combined in 50/50 mixture with the above di-(N-methylcarbamate) solution. The amounts used and the end points (MIC) obtained are set forth in the following table.

TABLE M'IC (p.p.m.) versus Bacteriostatic agent(s): S. aureus 1.95% di-carbamate 0.22

1% carbanilide 0.12 0.75% carbanilide 0.32 0.5% carbanilide 0.12 0.25% carbanilide 0.18

50/50 mixture of:

1.95% di-carbamate and 1% carbanilide 0.06 1.95 di-carbamate 1 and 0.75 carbanilide 2 0.10 1.95% di-carbmate and 0.5% carbanilide 0.06 1.95 di-carbamate 1 and 0.25 carbanilide 2 0.10

2,2 methylene-bis-(3,4,6-tr1chlorophenol)-dt-(N-methylcarbamate).

2 3,3,4,4-tetrachlorocarbaulllde. It appears from the above results that the end points of the 3,3'4,4-tetrachlorocarbanilide are inconsistent. The above results have been thoroughly rechecked and replicated without altering the above inconsistency. Although we cannot explain what the actual mechanism of the synergistic effect is, it is clear that there is synergism between the di-(N-methylcarbamate) and the 3,3',4,4'-tetrachlorocarbanilide at each of the concentrations shown. The invention relates to the synergistic cooperation of these two agents when used in minor proportions in various compositions, especially detergent compositions such as soap, and the discovery that this synergistic phenomenon occurs even at the high pH conditions existing in soap and other detergent and cleansing formulations.

The results set forth in the foregoing example with respect to a specific soap (20% sodium coco and 80% sodium tallow soap) are obtained with soaps generally.

4 Thus, a fatty acid soap such as sodium laurate, potassium stearate, sodium oleate, and potassium myristate will also produce these results. Furthermore, the synergistic action is independent of the soap medium and will take place in non-detergent media as well as in anionic detergent other than soap and in nonionic detergent systems. At the same time, soap is a system in which the synergistic components are highly effective and useful.

The term soap refers to the water-soluble ammonium, phosphorus, metallic or organic base (such as alkyl or alkoxy-alkyl containing up to about 9 carbon atoms) salts of various fatty acids or long chain synthetic acids wherein long chain refers to aliphatic radicals containing from about 12 to 22 carbon atoms. Such aliphatic radicals may be principally dodecyl, tetradecyl, hexadecyl and octadecyl; and the fatty acids may be chiefly lauric, oleic, stearic and palmitic acids. As used in this description, the term is intended to cover all products in which soap is a major constituent, for example bar, flake, powder, gel and liquid soap; shaving cream; toothpaste; facial and cleansing cream; and the like.

Further the soap ingredient may be partially, substantially or completely replaced with anionic type and nonionic type synthetic detergents. The anionic type synthetics suitable for use in the present invention can be described as those detergents having pronounced cleansing power and including in their molecular structure an alkyl radical containing from 6 to 18 carbon atoms and a sulfonic acid or sulfuric acid ester radical. Either organic base, ammonium, sodium or potassium salts of such anionie type detergents can be used. Principal types of detergents falling within this category are illustrated by alkylaryl sulfonates such as sodium or potassium dodecyl benzene sulfonate, sodium or potassium octadecyl benzene sulfonate, and sodium or potassium octyl naphthalene sulfonate; the alkyl sulfates such as sodium or potassium salts of dodecyl, hexadecyl, and octadecyl sulfates; the sulfonated fatty acid amides such as sodium or potassium salts of the oleic acid amide of methyl taurine; and the sulfonated monoglycerides such as the mono-coconut oil fatty acid ester of sodium 1,2-hydroxypropane-3-su1fonate.

Suitable nonionic type synthetic detergents for use in the present invention can be described as those detergents which do not ionize in solution but owe their water-solubility to un-ionized polar groups such as hydroxy, oxyethyl or other linkages. Principal types of detergents falling within this category are illustrated by the polyoxyethylene ethers of the higher fatty alcohols and alkyl phenols; the polyethylene glycols of fatty acid; fatty alkylol amide condensation products; polymers of ethylene and propylene oxides; compounds formed by the addition of propylene oxide to ethylene diamine followed by addition of ethylene oxide; fatty acid ethylene oxide condensation product; condensation products of ethylene oxide and a fatty acid ester of a polyhydric alcohol or sugar; and the detergents prepared by heating together a higher fatty acid with a diethanolamine. Exemplary examples of such synthetic nonionic detergents suitable for the purpose of the present invention are ethylene oxide-tall oil fatty acid reaction products; isooctyl phenol-ethylene oxide reaction products, propylene oxide-ethylene oxide reaction products; and combinations of isooctyl phenol-ethylene oxide with coconut oil or the like fatty acid ethylene oxide reaction products.

Relatively small amounts of the components of our synergistic mixtures are sufiicient for the increased antibacterial effects in the detergent product. Satisfactory results can be obtained when the combined weights of the tetrachlorocarbanilide and the di-carbamate are from 0.10% to 5.0% of the total weight of the detergent composition. A preferred range is a weight concentration of about 0.21% to 4.2%, and an especially preferred product is one containing soap and 0.5 to 3% combined weight of the above components, by weight of the composition.

It should be understood that even concentrations below the ranges set forth above will provide some degree of antibacterial effects, and a substantially higher concentration than those referred to will also give satisfactory results, although there are economic and other practical considerations which limit the desirability of greater amounts of the antibacterial ingredients in the soap or other medium.

The synergistic combination of the 2,2'-methylene-bis- (3,4,6 trichlorophenyl) di (N methylcarbamate) and 3,3,4,4'-tetrachlorocarbanilide can be added to the soap and other detergents by any suitable method which results in a uniform distribution of the agents throughout the entire mass.

While this invention has been described and exemplified in terms of its preferred embodiments, those skilled in the art will appreciate that variations and modifications may be made without departing from the spirit and scope of the invention.

What is claimed is:

1. Antiseptic compositions consisting essentially of a detergent selected from the group consisting of water soluble soaps, nonionic synthetic organic detergents and anionic synthetic organic detergents and a synergistic combination of 3,3,4,4 tetrachlorocarbanilide and 2,2-methylene bis (3,4,6 trichlorophenol) di (N methylcarbamate), wherein ratio of said tetrachlorocarbanilide to said di-(N-methylcarbamate) in parts by weight is from UNITED STATES PATENTS 3,107,261 10/ 1963 Gerber et a1. 260 -453 3,404,207 10/ 1968 Baker et a1. 424-300 3,503,886 3/1970 Casely et a1. 252-107 3,651,128 3/1972 Nikawitz 260479 C FOREIGN PATENTS 733,776 5/ 1969 Belgium.

LEON D. ROSDOL, Primary Examiner P. E. WILLIS, Assistant Examiner US. Cl. X.R. 252-106 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION 3,7 3,M7l lmted November 21, 1972 Patent No.

Inventor(s) Moneeb Zakaria et al It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In claim L, line 11, the Word "nonionic" should read anionic Signed and sealed this 2 +th day of April 1973 (SEAL) Attest:

EDWARD M. FLETCHER,JR. ROBERT GOTTSCHALK Attescing Officer Commissioner of Patents UscoMM-Dc 60376-P69 w u.s. sovsnumzm PRINTiNG OFFICE: was 0-366-334 F ORM PO-1050 (10-69) 

